This invention relates to the preparation of certain quinazoline compounds as well as intermediates thereof. The quinazolines prepared by the process of the present invention inhibit the action of certain growth factor receptor protein tyrosine kinases (PTK) thereby inhibiting the abnormal growth of certain cell types. These quinazolines are anti-cancer agents and are useful for the treatment of cancer in mammals.
Protein tyrosine kinases are a class of enzymes that catalyze the transfer of a phosphate group from ATP to a tyrosine residue located on a protein substrate. Protein tyrosine kinases clearly play a role in normal cell growth. Many of the growth factor receptor proteins function as tyrosine kinases and it is by this process that they effect signaling. The interaction of growth factors with these receptors is a necessary event in normal regulation of cell growth. However, under certain conditions, as a result of either mutation or overexpression, these receptors can become deregulated; the result of which is uncontrolled cell proliferation which can lead to tumor growth and ultimately to the disease known as cancer [Wilks A. F., Adv. Cancer Res., 60, 43 (1993) and Parsons, J. T.; Parsons, S. J., Important Advances in Oncology, DeVita V. T. Ed., J.B. Lippincott Co., Phila., 3 (1993)]. Among the growth factor receptor kinases and their proto-oncogenes that have been identified and which are targets of the compounds of this invention are the epidermal growth factor receptor kinase (EGF-R kinase, the protein product of the erbB oncogene), and the product produced by the erbB-2 (also referred to as the neu or HER2) oncogene. Since the phosphorylation event is a necessary signal for cell division to occur and since overexpressed or mutated kinases have been associated with cancer, an inhibitor of this event, a protein tyrosine kinase inhibitor, will have therapeutic value for the treatment of cancer and other diseases characterized by uncontrolled or abnormal cell growth. For example, overexpression of the receptor kinase product of the erbB-2 oncogene has been associated with human breast and ovarian cancers [Slamon, D. J., et. al., Science, 244, 707 (1989) and Science, 235, 1146 (1987)]. Deregulation of EGF-R kinase has been associated with epidermoid tumors [Reiss, M., et. al., Cancer Res., 51, 6254 (1991)], breast tumors [Macias, A., et. al., Anticancer Res., 7, 459 (1987)], and tumors involving other major organs [Gullick, W. J., Brit. Med. Bull., 47, 87 (1991)]. Because the importance of the role played by deregulated receptor kinases in the pathogenesis of cancer, many recent studies have dealt with the development of specific PTK inhibitors as potential anti-cancer therapeutic agents [some recent reviews: Burke. T. R., Drugs Future, 17, 119 (1992) and Chang, C. J.; Geahlen, R. L., J. Nat. Prod., 55, 1529 (1992)].
This invention provides a process for preparing a compound of formula 1: 
wherein:
X is phenyl optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, amino, and alkanoylamino of 1-6 carbon atoms;
R and R1 are each, independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, or trifluoromethyl;
R2 is hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, trifluoromethyl; 
R3 is independently hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, or carboalkyl of 2-7 carbon atoms;
n=2-4;
or a pharmaceutically acceptable salt thereof, with the proviso that each R3 of Y may be the same or different, which comprises:
a) acylating a compound of the formula: 
xe2x80x83with an acid chloride or mixed anhydride having the formula: 
xe2x80x83wherein
Z is xe2x80x94OR4, xe2x80x94SR4, xe2x80x94SOR4, xe2x80x94SO2R4, halogen, xe2x80x94NHR5, or xe2x80x94NR5R5;
R4 is all of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, or phenyl;
R5 is alkyl of 1-6 carbon atoms or cycloalkyl of 3-8 carbon atoms;
L is Cl, Br, or xe2x80x94OC(O)R6;
R6 is alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, or phenyl;
R3 and n are as defined above;
b) reacting the acylated product of step a) with H2Nxe2x80x94X,
xe2x80x83wherein
X is as defined above; and
c) treating the compound of step b) with a mild base to give the compound of Formula 1.
The preparation of compounds of Formula 1 and use as antineoplastic agents have been disclosed in U.S. Pat. No. 5,760,041, which is hereby incorporated by reference. The processes described herein provide a new method of preparing these compounds which does not produce polymerization of the vinyl moiety (of the compounds Formula 1), which occurred using the procedures described in U.S. Pat. No. 5,760,041.
The alkyl moieties described herein include both straight chain as well as branched carbon chains. Carboxy is defined as a xe2x80x94CO2H radical. Carboalkoxy of 2-7 carbon atoms is defined as a xe2x80x94CO2Rxe2x80x3 radical, where Rxe2x80x3 is an alkyl radical of 1-6 carbon atoms. Carboalkyl is defined as a xe2x80x94CORxe2x80x3 radical, where Rxe2x80x3 is an alkyl radical of 1-6 carbon atoms. When X is substituted, it is preferred that it is mono-, di-, or tri-substituted, with monosubstituted being most preferred. When a compound produced by the processes of this invention contains an assymetric center, this invention covers the individual R and S entantiomers as well as the racemate with respect to such compound. The pharmaceutically acceptable salts of compounds of Formula 1 are those derived from such organic and inorganic acids as: acetic, lactic, citric, tartaric, succinic, maleic, malonic, gluconic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, and similarly known acceptable acids. The pharmaceutically acceptable salts can be prepared from the corresponding free base compounds using standard chemical methodology.
Of the compounds of this invention, preferred members include those in which R, R1, and R2 are hydrogen; and those in which R, R1, and R2 are hydrogen and X is either unsubstituted or monosubstituted with halogen or alkyl of 1-6 carbon atoms. Preferred Z moieties include xe2x80x94OR4, xe2x80x94SR4, xe2x80x94SOR4, xe2x80x94SO2R4, halogen, where R4 is alkyl of 1-6 carbon atoms. It is also preferred that the acylating agent has the formula: 
The following scheme illustrates the preparation of compounds of Formula 1; the preferred acylating agent is exemplified in this scheme. The starting materials used in this synthesis are either commercially available or can be prepared using standard chemical methodology. For example, the starting imino aniline can be prepared from the nitrophenyl imine disclosed in U.S. Pat. No. 5,760,041. 
The acylating agent in the first step can either be an acid halide or can be a mixed anhydride. When the acylating agent is a mixed anhydride, the mixed anhydride can either be prepared as a separate step, or more preferably made in situ. The acylation reaction is typically carried out in the presence of a mild base, such as N-methyl morpholine, diisopropyl ethylamine, pyridine, and triethylamine.
In the second step, a Dimroth type rearrangement [Synthesis, 851(1988); Heterocyclic Chem., 16, 33(1974); Tetrahedron, 28, 535(1972); Z. Chem., 9, 241(1969)] can be carried out using a suitable solvent such as acetic acid, water, monohydric alcohols such as ethanol or isopropyl alcohol, or DMF, at temperatures ranging from ambient temperature to reflux. It is preferred that the reaction be carried out at temperatures above 78xc2x0 C. Acetic acid at reflux were found to be the preferred conditions to effect this transformation.
Elimination of HL to provide compounds of Formula 1 could be accomplished under mild conditions which prevented polymerization of the final product using bases such potassium ethoxide, potassium t-butoxide, primary, secondary, or tertiary alkoxide bases, or sodium carbonate in solvents such as ethanol, DMF, DMSO, THF, dioxane, methyl t-butyl ether, or diisopropyl ether. Acceptable reaction temperatures ranged from ambient to reflux. It is preferred that the elimination reaction be carried out using potassium t-butoxide in DMF at ambient temperature. It also preferred that at least three molar equivalents of base be used in this reaction. Alternatively, the elimination reaction could be accomplished using Lewis Acids such as ZnCl2, nBu4NF, CuSO4, BF3.Et2O, or Yb(OTf)3 in solvents such as nitrobenzene, nitromethane, carbon disulfide, or chlorinated hydrocarbons, such as dicloromethane or chloroform.
Scheme II shows the preparation of 4-(3-bromophenylamine)-6-(vinylamide)quinazoline), a representative compound of Formula 1, using the methodology described above. The preparation and antineoplastic activity of 4-(3-bromophenylamine)-6-(vinylamide)quinazoline) were disclosed in U.S. Pat. No. 5,760,041. 
The first two steps of Scheme 2 can also be carried out as a one pot synthesis where X is O or S, thereby eliminating the need for isolation of compound (6).
Alternatively, 4-(3-bromophenylamine)-6-(vinylamide)quinazoline) was prepared by converting the methyl sulfide (7) the corresponding sulfoxide (12) or sulfone (13), followed by mild basic elimination of the better leaving group. Conversion to the sulfoxide was accomplished with one mole of m-chloroperbenzoic acid in THF/DMF at xe2x88x9250xc2x0 C. to ambient temperature. Other oxidants such as hydrogen peroxide and Caro""s acid also provided satisfactory results. The corresponding sulfone was prepared from the methyl sulfide using OXONE (potassium peroxymonosulfate) in THF/methanol/water. The sulfone was also prepared using at least two molar equivalents of other oxidizing agents such as hydrogen peroxide, chlorine, ozone, or m-chloroperbenzoic acid. As 4-(3-bromophenylamine)-6-(vinylarnide)quinazoline) is useful as an antineoplastic agent, the compounds of Examples 1, 2, 4, 5, 7, 8, and 9 are useful as intermediates in its preparation.